HIV is entirely dependent on the virally encoded protease to achieve proper processing of its capsid proteins and enzymes. Therefore, the HIV-1 aspartic protease is one of the major targets for anti-viral agents for the treatment of AIDS. Several compounds have been developed and shown to be potent specific inhibitors of HIV-1 protease in vitro. A subset of these inhibitors are now in clinical trials. Unfortunately, beneficial effects of the drugs are proving to be short-term due to the emergence of resistant viral strains. The resistance can be conferred by several mutations in the protease gene. As an alternative to small molecule inhibitors of protease, we are developing a macromolecular inhibitor, with the help of the Computer Graphics facilities, based on the ability of defective gene products to interfere with the function of wild-type gene products in vivo. HIV-1 protease is ideal for this application because it consists of two identical subunits and dimerization is a prerequisite for activity: each monomer contributes one catalytic aspartyl residue to the active site of the enzyme. Introducing a gene which codes for a catalytically defective protease into infected cells would result in catalytically defective heterodimer formation and production of non-infectious virus particles. We feel that such a gene therapy approach may provide an alternative to small molecule inhibitors and may prove to be less sensitive to resistance.